This is a proposal to renew funding of the Center for Drug Use and HIV Research (CDUHR) for years 21- 25. Recent advances in HIV biomedical and behavioral science have been shown to reduce HIV incidence and allow HIV-positive persons to reach near-normal lifespans. These achievements have led UNAIDS, the US and several local governments to propose strategies for ?Ending the HIV Epidemic?. Notwithstanding these successes, attaining this goal among people who use drugs (PWUD) will require addressing a number of important existing barriers. The overall theme of this renewal is ?Ending HIV/AIDS among People who use Drugs: Overcoming Challenges?. We define Ending HIV/AIDS as reducing new infections and increasing the proportion of PWUD who are virally suppressed. To accomplish this, we have identified these research priorities, which directly address the most significant challenges: (1) Devise new strategies to overcome emerging and persistent barriers to ending HIV/AIDS among PWUD. Barriers include recent increases in prescription opioid misuse, which have given rise to a new generation of heroin user and injectors, and lack of attention to the key role of substance use in new infections in men who have sex with men and heterosexuals. HIV-positive PWUD also experience disparities all along the continuum of HIV care, including delayed diagnosis, lower retention in care, delayed initiation of ART and poorer disease outcomes. (2) Conduct research on effective ways to broadly implement evidence-based interventions. HIV prevention and care programs for PWUD do not exist in many regions of the US and the rest of the world where they are needed most, and they are rarely implemented at public-health scale. (3) Develop new, innovative models of prevention and treatment interventions to address substance-use related disparities in HIV infection and treatment outcomes that take into account the complex, multilevel nature of HIV among PWUD. We have made significant changes in our scope and structure for this renewal, and we will achieve our aims through five Cores, an Administrative Core and four Research Support Cores: (1) Infectious Disease Epidemiology and Theory, (2) Transdisciplinary Research Methods, (3) Dissemination and Implementation, and (4) Pilot Projects and Mentoring. These Cores support our research base and affiliated investigators to conduct cutting-edge science and enhance synergy across investigators from multiple disciplines, thereby leading to contributions to the field that are beyond what the individual projects could have achieved. In addition to the many successful initiatives that have been developed over CDUHR's history, new activities were added to respond to the evolving needs of our investigators. Also, in addition to our ongoing commitment to train new investigators to conduct high-impact research, we will collaborate with investigators in areas where HIV epidemics are occurring among PWUD (in rural and middle America, and in eastern Europe and Asia), building on our collective knowledge and expertise to advance toward Ending HIV/AIDS in those regions.